title: The WD40-repeat protein-containing deubiquitinase complex: catalysis, regulation, and potential for therapeutic intervention.
abstract: Ubiquitination has emerged as an essential signaling mechanism in eukaryotes. Deubiquitinases (DUBs) counteract the activities of the ubiquitination machinery and provide another level of control in cellular ubiquitination. Not surprisingly, DUBs are subjected to stringent regulations. Besides regulation by the noncatalytic domains present in the DUB sequences, DUB-interacting proteins are increasingly realized as essential regulators for DUB activity and function. This review focuses on DUBs that are associated with WD40-repeat proteins. Many human ubiquitin-specific proteases (USPs) were found to interact with WD40-repeat proteins, but little is known as to how this interaction regulates the activity and function of USPs. In recent years, significant progress has been made in understanding a prototypical WD40-repeat protein-containing DUB complex that comprises USP1 and USP1-associated factor 1 (UAF1). It has been shown that UAF1 activates USP1 through a potential active-site modulation, and the complex formation between USP1 and UAF1 is regulated by serine phosphorylation. Recently, human USPs have been recognized as a promising target class for inhibitor discovery. Small molecule inhibitors targeting several human USPs have been reported. USP1 is involved in two major DNA damage response pathways, DNA translesion synthesis and the Fanconi anemia pathway. Inhibiting the USP1/UAF1 deubiquitinase complex represents a new strategy to potentiate cancer cells to DNA-crosslinking agents and to overcome resistance that has plagued clinical cancer chemotherapy. The progress in inhibitor discovery against USPs and the WD40-repeat protein-containing USP complex will be discussed.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, 214A Drake Hall, Newark, DE 19716, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Villamil
authors.forename: Qin
authors.initials: Q
authors.lastname: Liang
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D029681:Arabidopsis Proteins / Q000378:metabolism; D055162:Biocatalysis; D004260:DNA Repair; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism*
chemical_list: D029681:Arabidopsis Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D025801:Ubiquitin; D064570:Ubiquitin-Specific Proteases; C526165:WDR48 protein, human; C118067:WDR1 protein, human; C579228:USP1 protein, human